The role of positive costimulatory molecules in transplantation and tolerance

The manipulation of costimulatory pathways holds tremendous potential for treating immunologically mediated diseases. In this article, we review the role of molecules that deliver a positive second signal that, together with an antigen-specific signal from the T-cell receptor, is necessary to promote complete T-cell activation, differentiation and development of effector function.

Numerous positive costimulatory molecules have been identified: CD28/B7, induced costimulatory/induced costimulatory ligand, CD40/CD154, OX40/OX40L, CD27/CD70, 4-1BB/4-1BBL, LIGHT/herpes virus entry mediator, glucosyltransferase R and T-cell immunoglobulin mucin molecules. Many of these have been only recently discovered and remain incompletely studied. Recent work has demonstrated that some costimulatory molecules bind ligands expressed by nonprofessional activated protein C, some modulate regulatory T cells and some sustain rather than initiate immune responses. Emerging data suggest that the costimulatory pathways are redundant and that the various costimulatory molecules affect different T-cell populations and act at different times during the course of the immune response.

These observations suggest that the therapeutic exploitation of strategies targeting costimulatory molecules will require carefully timed interventions directed against multiple pathways.